The aim of this project is to study the neurobiological basis of the heterogenity seen in severely depressed individuals, and in particular in their resistance to treatment with anti-depressants. Our approach is to focus on unique patterns of responsiveness within the Limbic Hypothalamic Pituitary Adrenal (LHPA) axis of depressed individuals and to ascertain how these differences relate both to the functioning of a specific serotonin receptor (SHT1a) and to responsiveness (or resistance) to an anti-depressant drug that modulates the serotonin system (fluoxetine)> The 5HT1a receptor has been implicated in the mode of action of anti-depressants. Our working hypotheses is that chronic alterations in the stress system, especially basal levels of cortisol, can lead to changes in the expression of this receptor, especially in the hippocampus and in the prefrontal cortex. In particular, we propose that the 5HT1a receptor is sensitive to chronic elevations in glucocorticoids, and propose to test this in control subjects, using PET neuroimaging. Moreover, we suggest that the link between the stress and the serotonin extends to patients suffering from major depression. Thus, we plan to link the degree of dysregulation in the LHPA to the degree of resistance to treatment with fluoxetine, and to the alterations in the expression of 5HT1a receptor in particular brain regions. Together, the studies in this project will allow us for the first time to relate the heterogeneity in the neuroendocrine and treatment response to a "neuronal phenotype" (in this case, imaging a brain receptor") and to begin to explore the biological basis of individual differences in depression and its amenability to treatment.